NMPA issues the Announcement on Issues Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision

As per the Opinions of the General Office of the CPC Central Committee and the General Office of the State Council on Deepening the Reform of Review & Approval System to Encourage Innovation in Drugs and Medical Devices (General Office [2017] No. 42), and the Announcement on Adjusting the Review & Approval Items of APIs, Pharmaceutical Excipients and Packaging Materials (Announcement No. 146 of 2017) issued by the former CFDA, on July 16, 2019, NMPA issued the Announcement on Issues Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision, to further clarify the administrative details for associated review & approval and supervision of APIs, pharmaceutical excipients, packaging materials and containers in direct contact with pharmaceuticals (hereinafter referred to as AEP: APIs+ excipients + packaging) with drugs/preparations. 

I. Overall requirements 

(1) The use of AEP must comply with the medicinal requirements, mainly referring to the quality, safety and function of AEP should meet the needs of the pharmaceutical preparation. The review & approval of AEP and drug/preparation associated registration shall be registered on the registration platform by AEP registrant, and the drug/preparation registration applicant shall associate the data with the platform registration data when submitting the registration application; for AEPs that cannot be registered on the platform for special reasons, it is also possible for drug/ preparation registration applicants to provide the AEP research dossiers together with the application for drug/preparation registration. 

(2) AEP registrant is responsible for maintaining the registration information of the registration platform, and for the authenticity and completeness of the registration information. AEP supplier, as AEP registrant, shall register the product voluntarily. The overseas AEP suppliers may be registered by their resident representative offices in China, or entrusted Chinese agencies. The registration information shall be in Chinese, and the overseas AEP supplier and agency shall be jointly responsible for the authenticity and completeness of the registration information. 

(3) When applying for registration of a drug/preparation, the applicant must provide the AEP registration number and the authorization letter of AEP registrant. 

(4) The applicant for drug/preparation registration or the Marketing Authorization Holder bears the principal responsibility for drug quality. According to the relevant requirements for drug registration and post-marketing production management, the quality management system of AEP supplier shall be audited to ensure compliance with the requirements of drug use. 

(5) The regulatory department shall be responsible for the confidentiality of the technical information submitted by AEP registrant, as well as the technical information of the registration platform. The registration platform shall disclose only the registered variety's registration status indicator (A or I), registration number, variety name, company/agency name, production address, the original drug approval number (if any), the validity period of the original approval document (if any), product source, specification, update date and other necessary information. 

II. Product registration management 

(6) AEP registrant shall register on the platform per the technical requirements of the registration dossiers, and obtain the registration number. APIs should, prior to registration, obtain the Drug Manufacturing Certificate within the corresponding production scope, and register in accordance with the Announcement on Promulgating the Requirements for Application Dossiers of Chemicals in New Registration Classifications (Interim) (CFDA Announcement No. 80 of 2016); pharmaceutical excipients and pharmaceutical packaging materials shall be registered per the data requirements of Annex 1 and Annex 2 of this Announcement. The technical requirements for registration dossiers shall be continuously improved according to industrial development and scientific and technological progress, and updated and announced in due course by CDE of NMPA (hereinafter referred to as CDE). 

(7) The application for registration of the drug/preparation shall be associated with the registered AEP. Where the drug/preparation is approved, it indicates that its associated AEP has also passed the technical review, and marked as A on the registration platform; where the technical review failed or the association is unestablished, the identifier shall be I. 

(8) Except for AEPs phased out, cancelled, or prohibited by the state from being used, AEP that meets the following conditions shall be transferred to the registration platform by CDE and the registration number shall be given, and the registration status shall be marked as A: 

1. APIs with an expiration date of the approval/proof document no earlier than November 27, 2017;    

2. APIs that have been accepted and completed for review and approval, including the application for technology transfer of APIs reviewed by the provincial administration in accordance with the CFDA Department of Drug Registration [2013] No. 38 Document; 

3. Pharmaceutical excipients and pharmaceutical packaging materials whose applications have been accepted and completed for review; 

4. Pharmaceutical excipients that once obtained approval documents; 

5. Pharmaceutical packaging materials with an expiration date of the approval/proof document no earlier than August 10, 2016. 

AEP registrant transferred to the registration platform shall submit the research materials on the platform per the requirements for registration dossiers stated herein, enrich the registration information, and submit the data consistency commitment letter (claiming that the technical data submitted by the registration platform is consistent with that of the registration approval). 

(9) For APIs of generics or imported drug/preparation domestically marketed, after the registration of the API registrants, they may be subject to separate review and approval, and the registration status of the passed review & approval shall be marked as A, otherwise: I. The time limit and requirements for review and approval shall comply with the Provisions for Drug Registration and other relevant regulations. 

(10) Pharmaceutical excipients with longterm usage in foods and medicines and recognized safety (see Annex 3 for details of the list) can do without registration, the applicants for registration of drug/preparation shall list the product list and basic information in the preparation application dossiers. However, where CDE considers it necessary during the review process of drug/preparation registration application, it may request the applicant to provide the corresponding technical information. The list of such medicinal excipients shall be updated by CDE in due course. 

(11) Administrative licenses have been cancelled for pharmaceutical excipients and pharmaceutical packaging materials, thence no fees are charged for platform registration. APIs, however, are still subject to administrative licenses, and the relevant requirements for platform registration and technical review are implemented in accordance with current regulations and standards. 

III. The use and management of AEP registration information 

(12) Where the research materials of AEP registration platform cannot meet the needs in the associated review of application for registration of drug/preparation, CDE may require the applicant or the original registrant to supplement dossiers. The means of submission of supplementary information shall be specified by CDE in the notice for supplementary information. 

(13) Where the API is marked as A, it indicates that the API has passed the review and approval. The APIs registrant can print the approval/proof document, quality standards and labels etc. via the registration platform voluntarily for GMP inspection and import customs clearance. 

For APIs not registered on the platform and whose research materials are submitted together with the drug/preparation registration application dossiers, the regulatory department shall indicate the relevant APIs information in the drug/preparation approval document, which may be used for the GMP inspection of APIs and import customs clearance. 

(14) The procedures and requirements of APIs manufacturers' application for GMP inspection shall comply with the relevant provisions of the current laws and regulations, and the registration information shall be updated on the registration platform after passing the drug GMP inspection. 

(15) Where a technical change of APIs identified as A occurs, an application for change shall be submitted in accordance with the relevant provisions on the current drug registration management, and shall be implemented after approval. Other changes in APIs, changes in pharmaceutical excipients and pharmaceutical packaging materials should be updated in a timely manner on the registration platform and summarized in the previous year's annual report submitted in the first quarter of each year. 

(16) Where any change arises for AEP, the AEP registrant shall initiate research on its own initiative, and promptly notify the relevant drug/preparation production enterprise (Drug Marketing Authorization Holders), update the registration information in a timely manner and specify it in the annual report. 

After receiving the above notice, the drug/preparation manufacturer (Marketing Authorization Holder) shall promptly evaluate or study the impact of the corresponding change on the quality of the drug/preparation, if quality is affected, it shall file a supplementary application. 

(17) Where the AEP and AEP supplier of marketed pharmaceutical preparations are subject to change, research shall be conducted following the Technical Guidelines for Studies on the Alterations of Post-Marketed Chemicals (I), Technical Guidelines for Studies on the Production Process Alterations of Post-Marketed Chemicals, and Technical Guidelines for Studies on Alterations of Post-Marketed TCMs (I), as well as the relevant provisions on the current drug registration management. 

(18) Where the overseas AEP supplier replaces the registration agency, it shall be changed after submitting relevant documents and materials, including: explanation of reasons for change, letter of entrustment by overseas AEP supplier along with its notarized document and its Chinese translation, copy of business license of new agency, document of foreign AEP supplier to cancel the entrustment relationship of the original agency along with its notarized document and Chinese Translation. 

IV. Supervision and management 

(19) The drug regulatory authorities of the provinces (autonomous regions and municipalities) shall, after the marketing of the APIs with the registration status marked A, conduct post-marketing management according to the drugs, and carry out drug GMP inspections. 

(20) The drug regulatory authorities of the provinces (autonomous regions and municipalities) shall strengthen the supervision and inspection of drug/preparation enterprises (Drug Marketing Authorization Holder) within their respective administrative regions, supervise and urge drug/preparation enterprises (Drug Marketing Authorization Holder) to perform supplier audit responsibility for APIs, pharmaceutical excipients and pharmaceutical packaging materials. 

For pharmaceutical excipients and pharmaceutical packaging materials manufacturers holding the Drug Manufacturing Certificate, they shall continue to be managed according to the original administrative requirements. After the Certificate expires, the site information shall be registered in accordance with the requirements of this Announcement. 

(21) The drug regulatory authorities of all provinces (autonomous regions and municipalities) shall strengthen supervision, inspection and extension inspection of suppliers of pharmaceutical excipients and pharmaceutical packaging materials according to the registration information. Where quality problems are spotted in the production of pharmaceutical excipients and pharmaceutical packaging materials, they shall be investigated and dealt with in accordance with the laws and regulations in a timely manner, the corresponding drug/preparation manufacturers (drug Marketing Authorization Holders) shall no longer use the relevant products, and the marketed products shall be subject to evaluation and disposal. The extended inspection shall be organized by the provincial administration where the drug/preparation manufacturer (drug Marketing Authorization Holder) is located. The daily inspection of suppliers of pharmaceutical excipients and pharmaceutical packaging materials shall be organized by the local provincial administration for joint inspection. 

On-site inspection of the production of pharmaceutical excipients shall be carried out in accordance with the GMP for Pharmaceutical Excipients (SFDA Department of Drug Supervision [2006] No. 120). The on-site production inspection of the pharmaceutical packaging materials shall follow the General Rules for Production Site Inspection of Pharmaceutical Packaging Materials attached to the Measures for the Administration of Packaging Materials and Containers for Direct Contact with Medicines (Former SFDA Order No. 13). The drug regulatory authorities of various provinces (autonomous regions and municipalities) may further improve relevant technical specifications and inspection standards according to regulatory needs, and promote the steady improvement of the quality of excipients and pharmaceutical packaging materials. 

NMPA shall revise the relevant inspection standards in due time according to the situation and needs of various provinces' supervision and inspection. 

V. Others 

(22) APIs, pharmaceutical excipients and pharmaceutical packaging materials developed, produced, imported and used within the territory of the People's Republic of China shall be applicable to the requirements of this Announcement. 

(23) This Announcement shall come into force as of August 15, 2019. Where the original documents related to AEP are inconsistent with the requirements of this Announcement, this Announcement shall prevail. The Announcement on the Release of Requirements for Application Dossiers of Pharmaceutical Packaging Materials and Pharmaceutical Excipients (Interim) (Announcement No. 155, 2016) issued by the former CFDA, shall be repealed simultaneously 

Annexes: 

1. Requirements for registration of medical excipients (Interim)(omitted)

2. Requirements for registration of medical packaging materials (Interim) (omitted)

3. Catalogue of products that can be exempted from registration (2019 edition) (omitted)

4. Basic requirements for the annual report of medicinal raw materials, excipients and pharmaceutical packaging materials (omitted)